S279: EFFECT OF VOXELOTOR ON CEREBRAL PERFUSION AND CEREBRAL OXYGEN METABOLISM IN ADULT PATIENTS WITH SICKLE CELL DISEASE; THE COVERAGE STUDY
Authors: Kadère Konté, Liza Afzali-Hashemi, Koen Baas, Anouk Schrantee, Erfan Nur, Aart Nederveen, Bart Biemond
Journal: HemaSphere (2023)

Background: Sickle cell disease (SCD) is characterized by haemolytic anaemia, vaso-occlusive painful crises and widespread organ complications. A severe complication is cerebral ischemia leading to overt strokes or silent cerebral infarctions. Patients with HbSS and HbSβ0-thalassemia have an increased cerebral blood flow (CBF) to maintain oxygen delivery (OD). But ultimately still a reduced cerebral metabolic rate of oxygen (CMRO2). Voxelotor, a small molecule reversibly binding to haemoglobin (Hb), increases its oxygen affinity, thereby decreasing HbS polymerization and sickling, resulting in decreased haemolysis and higher haemoglobin (Hb) levels. Aims: The aim of this study was to assess the effect of voxelotor on MRI-based markers of cerebral perfusion and oxygen metabolism. In addition, the effects of voxelotor on parameters of cardiac stress and hyperdynamic function were assessed. Methods: This single-arm, interventional trial was conducted at Amsterdam University Medical Centers, Amsterdam, The Netherlands. Adult SCD patients with the HbSS and HbSβ0-thalassemia genotypes were eligible for the study. Inclusion criteria were Hb levels ≤ 10.5 g/dL and in case of hydroxyurea use a stable dose for at least 90 days. Exclusion criteria were red blood cell transfusion within 90 days and hospitalization for VOC within 14 days prior to inclusion in this study. At baseline and after 3 months of voxelotor treatment (1500 mg QD), MRI scans, echocardiography and laboratory assessments were performed. Gray- and white matter (GM, WM) CBF were measured using time-encoded arterial spin labelling. Venous blood T2 in the superior sagittal sinus was measured using T2-relaxation-Under-Spin-Tagging. Oxygen delivery was calculated by multiplying CBF and oxygen content (calculated from Hb and arterial saturation by pulse oximetry). Subsequently, CMRO2 was calculated from the CBF, OEF and oxygen content. Hyperdynamic circulation and cardiac stress was assessed by measuring maximal tricuspid regurgitation velocity (TR Vmax) by trans-thoracic echocardiography and plasma levels of N-Terminal pro-B-type natriuretic peptide (NT-proBNP). Non-parametric data were described with median and IQR. Wilcoxon signed-rank tests were used. A p-value < 0.05 was considered statistically significant. Results: Eighteen adult SCD patients (HbSS/HbSβ0-thalassemia: 13/5) with a median age of 35 years (IQR 29 - 45) consisting of 12 males and 6 females successfully completed their baseline and 3 months follow-up measurements. Hb levels significantly increased from 7.6 to 9.8 g/dL (p = 0.001), corresponding to significant decreases in reticulocyte counts and LDH and bilirubin levels as markers of haemolysis (p = < 0.05; Table 1). A significant increase in oxygen delivery from 6.4 to 8.0 ml O2/100g/min (p = 0.002) was observed, primarily due to increased Hb levels. However, no significant changes were observed in GM and WM CBF, and CMRO2 (Table 2). OEF decreased from 29.6% to 23.5% (p = 0.002; Table 2). With respect to the parameters of cardiac stress, a significant decrease in NT-proBNP levels from 93 to 64 ng/L, (p = 0.048), was observed, while no effect on the median TR Vmax was observed (Table 1). Summary/Conclusion: Despite a profound increase in Hb levels and oxygen delivery after voxelotor treatment, CBF and CMRO2 were unaffected. These observations are most likely explained by the increased oxygen affinity induced by voxelotor resulting in decreased OEF compensating the effect of increased oxygen delivery. In contrast, the increased Hb resulted in reduced NT-proBNP levels suggesting improved cardiac performance.Keywords: Sickle cell, Sickle cell anemia, Sickle cell disease